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The Journal of Neuroscience, July 15, 2000, 20(14):5292-5299
Modulation of Interleukin-1 and Tumor Necrosis Factor  Signaling by P2 Purinergic Receptors in Human Fetal
Astrocytes
Judy S. H.
Liu1,
Gareth
R.
John1,
Andrew
Sikora2,
Sunhee C.
Lee1, and
Celia F.
Brosnan1, 3
Departments of 1 Pathology, 2 Microbiology
and Immunology, and 3 Neuroscience, Albert Einstein College
of Medicine, Bronx, New York 10461
In human astrocytes, interleukin-1 (IL-1) is a potent inducer
of genes associated with inflammation. In this study, we tested the
hypothesis that in primary cultures of human fetal astrocytes signaling
by the P2 purinergic nucleotide receptor pathway contributes to,
or modulates, cytokine-mediated signal transduction. Calcium imaging
studies indicated that most cells in culture responded to ATP, whereas
only a subpopulation responded to UTP. Pretreatment of astrocytes with
P2 receptor antagonists, including suramin and periodate oxidized ATP
(oATP), resulted in a significant downregulation of IL-1-stimulated
expression of nitric oxide, tumor necrosis factor (TNF ), and IL-6 at
both the protein and mRNA levels, without affecting cell viability. In
cells transiently transfected with reporter constructs, IL-1
demonstrated more potent activation of the transcription factors
nuclear factor - B (NF-B) and activator protein-1 (AP-1) than
TNF. However, pretreatment with oATP downregulated activation of
NF-B and AP-1 by IL-1 or TNF. Electromobility shift assays
using oligonucleotides containing specific NF-B binding sequences
confirmed that pretreatment with oATP or apyrase attenuated
cytokine-mediated induction of this transcription factor. From these
data, we conclude that P2 receptor-mediated signaling intersects with
that of IL-1 and TNF to regulate responses to cytokines in the
CNS. Because inflammation, trauma, and stress all lead to the release
of high levels of extracellular nucleotides, such as ATP and UTP,
signaling via P2 receptors may provide a mechanism whereby cells can
sense and respond to events occurring in the extracellular environment
and can fine tune the transcription of genes involved in the
inflammatory response.
Key words:
P2 receptors; IL-1; TNF; human fetal astrocytes; transcription factor NF-B; transcription factor AP-1
Copyright © 2000 Society for Neuroscience 0270-6474/00/20145292-08$05.00/0
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